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Synthesis 2007(21): 3361-3370  
DOI: 10.1055/s-2007-990820
PAPER
© Georg Thieme Verlag Stuttgart · New York

A Facile Synthesis of (n+3) and (n+4) Ring-Enlarged Lactones as well as of Spiroketolactones from n-Membered Cycloalkanones

Tarun K. Pradhan, Alfred Hassner*
Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
Fax: +972(3)7384053; e-Mail: hassna@mail.biu.ac.il;
Further Information

Publication History

Received 31 May 2007
Publication Date:
10 October 2007 (online)

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Abstract

We report detailed studies of the facile synthesis of functionalized 8-, 9-, 10-, 11-, and 15-membered-ring lactones from simple ethyl 1-allyl-2-oxocycloalkanecarboxylates, resulting from a three-atom ring enlargement. Similarly, four-atom ring enlargements of a 5- to 9- and 6- to 10-membered-ring lactones were achieved. Alkoxy radical fragmentation (ARF) with hypervalent iodine was used as the key step for these ring expansions. The ring enlargement proceeds via an unstable hemiketal intermediate, which was isolable in some cases. Where hemiketals were not isolated, molecular modeling calculations are consistent with the relative stability of hydroxy ketones vs. hemiketals. The same substrates can be diverted in an ionic pathway on reaction with iodine or bromine to afford spirolactones. The formation of spirolactones occurs in a highly stereoselective manner, apparently involving participation of the ester carbonyl group.

Keywords

spiro compounds - ring expansion - radical reaction - dia­stereoselectivity - lactone

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MM2 calculations, performed by CS Chem3D Pro version 5.0, Cambridge Soft Corporation, 100 Cambridge Park Drive, Cambridge, MA 02140.D, showed that bicyclic γ-hydroxy ketones intermediates 5, derived from 5-, 7-, 8-, and 12-membered rings, are more stable by 10, 9, 12, 8, kcal/mol respectively than their corresponding hemiketals of type 2, while in the 6-membered ring case the difference is approx 4 kcal. Similarly, δ-hydroxy ketones 10a and 10c are more stable by about 7 and 12 kcal/mol respectively than their corresponding hemiketals. Though these are only simple gas phase calculations they provide relative energies for isomer pairs.

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These results are consistent with ab initio calculations by A. M. Belostotskii, to be reported separately.